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WO1993006865A1 - Traitement de l'inflammation oculaire par blocage des molecules d'adhesion cellulaire - Google Patents

Traitement de l'inflammation oculaire par blocage des molecules d'adhesion cellulaire Download PDF

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Publication number
WO1993006865A1
WO1993006865A1 PCT/US1992/008556 US9208556W WO9306865A1 WO 1993006865 A1 WO1993006865 A1 WO 1993006865A1 US 9208556 W US9208556 W US 9208556W WO 9306865 A1 WO9306865 A1 WO 9306865A1
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WO
WIPO (PCT)
Prior art keywords
inflammation
icam
cell adhesion
expressed
eye
Prior art date
Application number
PCT/US1992/008556
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English (en)
Inventor
Scott M. Whitcup
Chi-Chao Chan
Robert B. Nussenblatt
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The United States of America, represented by The Secretary, Department of Health & Human Services
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Application filed by The United States of America, represented by The Secretary, Department of Health & Human Services filed Critical The United States of America, represented by The Secretary, Department of Health & Human Services
Priority to JP50717493A priority Critical patent/JP3679112B2/ja
Priority to DE69229275T priority patent/DE69229275T2/de
Priority to EP92921907A priority patent/EP0610290B1/fr
Priority to CA002120506A priority patent/CA2120506C/fr
Publication of WO1993006865A1 publication Critical patent/WO1993006865A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2851—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72
    • C07K16/2854—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72 against selectins, e.g. CD62
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2821—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against ICAM molecules, e.g. CD50, CD54, CD102
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
    • C07K16/2845—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily against integrin beta2-subunit-containing molecules, e.g. CD11, CD18
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates, in general, to a method of blocking cell adhesion molecules.
  • the present invention relates to a method of blocking cell adhesion molecules with monoclonal
  • Cell adhesion molecules are surface proteins that mediate cell binding, and the expression of these molecules can promote the migration of leukocytes to areas of inflammation.
  • ICM-1 intercellular adhesion molecule-1
  • Lymphocyte function-associated antigen-1 (LFA-1), a member of the integrin family of cell adhesion molecules, is the counter receptor for ICAM-1. In contrast to ICAM-1 which can be expressed on several ocular tissues, LFA-1 is
  • ELAM-1 endothelial leukocyte adhesion molecule-1
  • the goal of the present invention is to demonstrate that cell adhesion molecules are expressed on tissues in the eye during ocular inflammation and to show that by blocking these cell adhesion molecules,
  • EIU endotoxin induced uveitis
  • EAU experimental autoimmune uveitis
  • FIG. 1 Immunohistochemical staining for LFA-1.
  • A Infiltrating lymphocytes in an area of retinal vasculitis stain intensely for LFA-l ⁇ . B: These same lymphocytes also stain intensely for LFA-1ß (original magnification ⁇ 200).
  • Figure 2. Immunohistochemical staining for ICAM- 1.
  • B The retinal vascular endothelium in an area of inflammation stains strongly for ICAM-1 (arrow) (original magnification ⁇ 400).
  • FIG. 4 Immunohistochemical staining for TNF- ⁇ . Inflammatory cells in the retina stain intensely for TNF- ⁇ (arrows) (original magnification ⁇ 400).
  • FIG. 1 Light micrograph of the ciliary body 10 hours after the injection of Salmonella typhimurium endotoxin. Immunostaining shows strong expression of ELAM-1 on the vascular endothelium (arrow) and on
  • Immunostaining shows strong expression of ELAM-1 on the corneal endothelium.
  • Inflammatory cells are adherent to the corneal endothelium where ELAM-1 is expressed (magnification ⁇ 400).
  • FIG. 7 a) funduscopy day 14, b) funduscopy day 21, and c) histology day 21.
  • Figure 9 Intraocular lens delivery of anti-adhesion molecule drugs, a) sustained release vehicle attached to optic, b) optic coated with anti-adhesion molecule drug.
  • Cell adhesion molecules are expressed on inflammatory cells and on ocular tissue.
  • the binding of cell adhesion molecules expressed on inflammatory cells to their corresponding counter-receptors expressed on ocular tissues fosters the development of inflammation in the eye.
  • monoclonal antibodies or synthesized molecules to block these cell adhesion molecules, ocular inflammation can be inhibited.
  • the present invention relates to a method of treating an animal with ocular inflammation comprising administering to said animal a therapeutically effective amount of an antibody or synthesized substance having binding affinity for a cell adhesion molecule under conditions such that said treatment is effected.
  • Suitable pharmaceutically acceptable diluents, carriers, and excipients are well known in the art.
  • Suitable amounts to be administered for any particular treatment protocol can readily be determined. Suitable amounts might be expected to fall within the range of 10 ⁇ g/dose to 10 g/dose, preferably within 10 mg/dose to 1 g/dose.
  • These substances may be administered by techniques known in the art (preferably systemically, via periocular injection, or topically to the eye as eye drops or ophthalmic ointment). This local administration can limit potential systemic side effects, but still allow control of ocular inflammation.
  • Current treatment of ocular inflammation centers around the use of steroids with a number of unwanted adverse effects such as glaucoma and cataract, which can be avoided with this new anti-inflammatory therapy for ocular inflammation.
  • the ocular inflammation results from trauma or disease.
  • the antibody or molecules to block adhesion molecules can be delivered by: 1. topical drops or ointment,
  • the ocular inflammation is post-surgical inflammation.
  • the antibody or molecules to block cell adhesion molecules can be delivered by:
  • the inflammation results from post-surgical corneal graft rejection.
  • the antibody or molecules to block cell adhesion molecules can be delivered by:
  • the ocular inflammation is posterior uveitis.
  • the antibody or molecules to block cell adhesion molecules can be delivered by:
  • periocular injection systemically by intravenous injection or orally
  • the present invention relates to a method of blocking a cell adhesion molecule in an animal comprising administering to said animal a sufficient amount of an antibody having binding affinity for said cell adhesion molecule such that blocking of said molecule is effected. More specifically, the present invention relates to a method of blocking cell adhesion molecules during ocular inflammation (preferably, the ocular inflammation is as described above).
  • the quantity of antibody used can be determined by one skilled in the art. The present invention is described in further detail in the following non-limiting Examples.
  • Case 4 A 38-year old white man developed bilateral granulomatous uveitis 6 months after a ruptured right globe secondary to blunt trauma (Chan, C-C. et al., Ophthalmology (1986) 93:690-5). The patient was diagnosed with sympathetic ophthalmia, and the right eye with bare light perception vision, was enucleated for pain control.
  • the primary antibodies included monoclonal antibodies against ICAM-1 (CD45) (Courtesy of Dr. Toshi Nakayama, National Cancer Institute, Bethesda, Maryland), LFA-l ⁇ (CDlla) and LFA-1B (CD18) (Becton Dickinson
  • EIU was induced in 59, female Lewis rats weighing 200 grams (Charles River, Wilmington, MA) in three separate experiments by injecting 100 ⁇ g of Salmonella typhimurium endotoxin (LPS) (Difco, Detroit, Michigan) into one footpad. All animals were treated in accordance with ARVO Resolution on Use of Animals in Research. Eyes were examined for clinical signs of inflammation under an operating microscope. Animals were then sacrificed and both eyes enucleated at 2 hour intervals from the time of injection until 48 hours post-injection. One eye was placed in 10% buffered formalin for routine
  • Formalin fixed eyes were embedded in methylmethacrylate and 3 micron thick sections were stained with hematoxylin-eosin. Immunohistochemical staining was performed on 5 micron frozen sections using an avidin-biotin-peroxidase complex (ABC) method (Kim, M.K. et al., Curr. Eye Res. (1986) 5:869).
  • the primary antibodies included 0X6 (anti-RTIB antibody) (Sea-lab Westbury, NY) and ELAM-1 (anti-human ELAM-1 that cross reacts with rat ELAM-1 courtesy of Dr. M. P. Bevilacqua).
  • ICAM-1 was uniformly expressed on the RPE in cases 2-6 ( Figure 2A), and expressed on some of the RPE cells in case 1. ICAM-1 was also expressed on the endothelium of blood vessels in the retina and choroid in areas of inflammation ( Figure 2B) of all 6 eyes with uveitis, and on glial cells in the retina (cases 2, 3, and 6). ICAM-1 and LFA-1 were not expressed constitutively on any cells in the control eyes. ELAM-1 was only expressed on the vascular endothelium in one eye with active sympathetic ophthalmia (case 4) ( Figure 3), but not in any other uveitic eye or in any of the control eyes.
  • LFA-1 was strongly expressed on the majority of inflammatory cells in the six eyes with uveitis.
  • LFA-1 also known as CD11a/CD18, is a member of the integrin family of cell adhesion molecules, and is expressed on leukocytes including T lymphocytes (Springer, T.A., Nature (1990) 346:425-434; Dustin, M.L. et al., J. Immunol.
  • Each integrin molecule is composed of an alpha and beta subunit.
  • the CD11a antibody is directed against the alpha subunit of LFA-1 and the CD18 antibody against the beta subunit.
  • the ligation of the T cell receptor causes the activation of LFA-1 in lymphocytes in an antigen specific manner (Turner, J.M. et al., Cell (1990) 60:755-765). This may be an important mechanism that allows blood cells to circulate unimpeded until they are activated at sites of inflammation, after the expression of cell adhesion molecules allows the cells to locate and make contact with the appropriate counter- receptor.
  • ICAM-1 The counter-receptor of LFA-1 is ICAM-1.
  • ICAM-1 In contrast to LFA-1 which is only expressed on leukocytes, ICAM-1 is found on a multitude of cells (Kishimoto, T.K. et al., Adv. Immuno. (1989) 46:149-182). In the eye, ICAM-1 may be weakly expressed constitutively on the corneal endothelium and cultured RPE (Elner, V.M. et al.. Am. J. Path. (1991) 138:525-536; Forrester, J.V. et al., Curr. Eye Res. (1990) 9 (Supp):183-191). ICAM-1 was found to be strongly expressed on the RPE, retinal and choroidal vascular endothelium, and on glial cells (M ⁇ ller cells) in the retina in eyes with clinical and histopathologic evidence of active uveitis.
  • ICAM-1 and LFA-1 are felt to be important for the binding of leukocytes to target cells. Inflammatory cells in the 6 eyes with active uveitis expressing LFA-1 were located adjacent to resident cells expressing ICAM-1. ICAM-1 was moderately to markedly expressed on the vascular endothelium and RPE of all 6 eyes with uveitis, and lymphocytes were only found
  • ICAM-1 adjacent to ICAM-1 expressing cells.
  • ICAM-1 was markedly and uniformly expressed on the RPE, and the adjacent choroid was infiltrated with LFA-1 expressing lymphocytes. In contrast, ICAM-1 was not uniformly
  • ICAM-1 expression may be integral to the migration of inflammatory cells into the choroid and retina and
  • ICAM-2 is also a ligand for LFA-1, and important for cell binding (Springer, T.A., Nature (1990) 346:425-434).
  • cytokines particularly by the infiltrating T lymphocytes, probably plays an important regulatory function.
  • Gamma- interferon, interleukin-1, and tumor necrosis factor cause the strong induction of ICAM-1, although different cells vary as to which cytokines will induce ICAM-1 expression (Kaminska, G.M. et al., Invest. Ophthalmol. Vis. Sci.
  • TNF-ß lymphotoxin
  • TNF-ß lymphotoxin
  • TNF- ⁇ was present in the areas of inflammation in all the uveitic eyes and may have increased ICAM-1 expression on the adjacent vascular endothelium. In contrast, 4 of 6 uveitic eyes stained weakly for the less active TNF-ß.
  • ELAM-1 is a cell surface-glycoprotein, expressed by cytokine-activated endothelium, that predominantly binds neutrophils
  • ELAM-1 expressed 2 hours after the local injection of endotoxin into the skin of baboons, and was absent by 9 hours after injection (Munro, J.M. et al., Lab. Invest. (1991) 64:295-299). This early and transient expression of ELAM-1 may explain why ELAM-1 expression was not present in these eyes with prolonged inflammation.
  • Sympathetic ophthalmia, VKH, sarcoidosis, and the subretinal fibrosis syndrome are all presumed autoimmune diseases of the eye.
  • the etiology of ocular inflammation in these disorders remains unknown, although an immune reaction against retinal antigens such as retinal S-antigen and interphotoreceptor binding protein may be causative in some cases.
  • the mechanism by which inflammatory cells migrate into the eye in uveitis is also not well documented.
  • ICAM-1 The demonstration of expression of ICAM-1 on the RPE, glial cells, and vascular endothelium and the presence of lymphocytes strongly expressing LFA-1 adjacent to these ICAM-1 expressing cells suggests that the ICAM-l/LAF-1 interaction is important in the development of ocular inflammation in these cases.
  • Antibodies against ICAM-1 and LFA-1 can significantly inhibit the binding of leukocytes, and monoclonal
  • SRFUS Subretinal fibrosis and uveitis syndrome
  • GL glial cells
  • SI site of inflammation
  • L lymphocyte
  • RPE retinal pigment eptheliun
  • neutrophils and monocytes were seen in the iris and ciliary body. Proteinaceous material, fibrin debris, and neutrophils were evident in the anterior chamber, with many neutrophils adherent to the corneal endothelium.
  • MHC class II antigen and ELAM-1 The time course for the expression of MHC class II antigen and ELAM-1 in the anterior segment of the eye following the induction of EIU are shown in Table 2.
  • MHC class II antigen was weakly expressed on one or two resident cells in the stroma of the ciliary body and iris.
  • MHC class II antigen was expressed on epithelial and stromal cells of the iris and the ciliary body.
  • Eight hours post-injection MHC class II antigen was expresssed on the corneal endothelium, and MHC class II antigen persisted on ocular tissue 48 hours after injection.
  • ELAM-1 did not appear to be expressed constitutively on any ocular tissue, but was first expressed on stromal and vascular endothelial in the iris and ciliary body 10 hours after the injection of LPS (Figure 5). ELAM-1 was later expressed on the corneal endothelium 22 hours post-injection ( Figure 6) . At this time, neutrophils were present in the anterior chamber, many adherent to the corneal endothelium where ELAM-1 was expressed. Between 24 and 48 hours after injection, expression of ELAM-1 on the corneal endothelium and cells in the ciliary body and iris gradually diminished.
  • ELAM-1 is an inducible cell adhesion molecule, which was expressed on vascular endothelial cells in the iris and ciliary body at the onset of EIU, and expressed on the corneal endothelium at the peak of inflammation.
  • ELAM-1 is cell surface
  • glycoprotein expressed by cytokine -activated
  • Endothelium in control skin did not express ELAM-1 but developed 2 hours after injection of endotoxin with concurrent extensive adhesion and extravasation of
  • ELAM-1 was first expressed in the eye 8 hours after injection of endotoxin and gradually diminished between 24 and 48 hours after injection. However, endotoxin was injected into the footpad of rats, therefore, the
  • Corneal and vascular endothelium are derived from different embryonic tissues. Corneal
  • ICM-1 intercellular adhesion molecule-1
  • HOURS Clinical and histopathologic evidence of disease 22 HOURS ELAM-1 expressed on the corneal endothelium
  • LPS lipopolysaccharide
  • EIU endotoxin-induced uveitis
  • Mac-1 (CD11b/CD18) is a cell adhesion molecule important for neutrophil and monocyte migration to arease of inflammation.
  • EIU endotoxin induced uveitis
  • mice were sacrificed 24 hours after endotoxin injection, and both eyes were enucleated. The right eye was processed for routine histopathology, and the left eye was snap frozen for immunohistochemistry. Histopathologic sections of the eyes were graded by two, masked observers on a scale of 0 (no inflammation) to 4+ (severe inflammation). The mean grade of ocular
  • antibodies against cell adhesion molecules can be used in treating ocular inflammation.
  • antibody against MAC-1 to prevent inflammation was used, however, similar results can be obtained using substances to block a wide array of these molecules.
  • the antibodies were administered systemically, but the treatment can be administered by a periocular injection or topically in the form of eye drops or
  • mice were immunized with 50 micrograms of IRBP and 0.25 mg of complete Freund's adjuvant by
  • mice were then divided into three groups receiving daily intraperitoneal injections containing 0.25 mg of anti-ICAM-1 antibody, anti-LFA-1 antibody, and rat IgG, respectively.
  • the fundi of these mice were examined under a dissecting microscope 14 and 21 days following injection of IRBP. All animals were sacrificed 21 days after injection of IRBP. One eye was placed in 4%
  • mice treated with daily intraperitoneal injections of monoclonal antibodies against ICAM-1 and LFA-1 developed less clinical evidence of ocular inflammation based on funduscopic examination 14 and 21 days after immunization with IRBP when compared to control animals treated with intraperitoneal rat IgG.
  • the funduscopic evidence of ocular inflammation was not only less severe, but
  • mice treated with antibodies to block ICAM-1 and LFA-1 developed less ocular inflammation than control animals. This study indicates that animals treated with monoclonal antibodies against ICAM-1 and LFA-1 develop ocular inflammation following the induction of

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Abstract

La présente invention concerne, en général, un procédé de blocage des molécules d'adhésion cellulaire. Plus précisément, la présente invention concerne un procédé de blocage des molécules d'adhésion cellulaire avec des anticorps monoclonaux ou des substances synthétisées.
PCT/US1992/008556 1991-10-04 1992-10-02 Traitement de l'inflammation oculaire par blocage des molecules d'adhesion cellulaire WO1993006865A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP50717493A JP3679112B2 (ja) 1991-10-04 1992-10-02 細胞接着分子の遮断による眼の炎症の治療
DE69229275T DE69229275T2 (de) 1991-10-04 1992-10-02 Herstellung eines arzneimittels zur behandlung von augenentzündung durch blockierung von zelladhäsionsmolekulen
EP92921907A EP0610290B1 (fr) 1991-10-04 1992-10-02 Obtention d'un medicament pour le traitement de l'inflammation oculaire par blocage des molecules d'adhesion cellulaire
CA002120506A CA2120506C (fr) 1991-10-04 1992-10-02 Traitement de l'inflammation oculaire par blocage de molecules d'adhesion cellulaire

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US770,026 1985-08-27
US77002691A 1991-10-04 1991-10-04
US82204292A 1992-01-17 1992-01-17
US822,042 1992-01-17

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WO1993006865A1 true WO1993006865A1 (fr) 1993-04-15

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US (1) US5597567A (fr)
EP (1) EP0610290B1 (fr)
JP (1) JP3679112B2 (fr)
AT (1) ATE180408T1 (fr)
AU (2) AU2777092A (fr)
CA (1) CA2120506C (fr)
DE (1) DE69229275T2 (fr)
WO (1) WO1993006865A1 (fr)

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WO1997031099A1 (fr) * 1996-02-22 1997-08-28 Icos Corporation SOUS-UNITE α DE L'INTEGRINE β HUMAINE
US5728802A (en) * 1992-05-06 1998-03-17 Affymax Technologies N.V. Peptides and compounds that bind selectins including endothelium leukocyte adhesion molecule 1 (ELAM-1)
WO2000040262A1 (fr) * 1999-01-05 2000-07-13 The Flinders University Of South Australia Nouveaux agents et methodes pour le traitement et le diagnostic de troubles oculaires
WO2001030386A1 (fr) * 1999-10-22 2001-05-03 Biogen, Inc. Utilisation d'un interrupteur de liaison cd40:cd154 pour le traitement de complications immunologiques de l'oeil
US11072661B2 (en) 2015-12-23 2021-07-27 Sorbonne Universite Agents that inhibit the binding of CFH to CD11 b/CD18 and uses thereof

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ES2614080T3 (es) 2005-05-17 2017-05-29 Sarcode Bioscience Inc. Composiciones y métodos para el tratamiento de trastornos oculares
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WO1997031099A1 (fr) * 1996-02-22 1997-08-28 Icos Corporation SOUS-UNITE α DE L'INTEGRINE β HUMAINE
WO2000040262A1 (fr) * 1999-01-05 2000-07-13 The Flinders University Of South Australia Nouveaux agents et methodes pour le traitement et le diagnostic de troubles oculaires
US6773916B1 (en) 1999-01-05 2004-08-10 The Flinders University Of South Australia Agents and methods for treatment and diagnosis of ocular disorders
WO2001030386A1 (fr) * 1999-10-22 2001-05-03 Biogen, Inc. Utilisation d'un interrupteur de liaison cd40:cd154 pour le traitement de complications immunologiques de l'oeil
US11072661B2 (en) 2015-12-23 2021-07-27 Sorbonne Universite Agents that inhibit the binding of CFH to CD11 b/CD18 and uses thereof

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CA2120506C (fr) 2000-12-12
AU1632297A (en) 1997-05-22
AU711480B2 (en) 1999-10-14
DE69229275D1 (de) 1999-07-01
CA2120506A1 (fr) 1993-04-15
DE69229275T2 (de) 1999-12-30
JP3679112B2 (ja) 2005-08-03
EP0610290B1 (fr) 1999-05-26
US5597567A (en) 1997-01-28
EP0610290A1 (fr) 1994-08-17
ATE180408T1 (de) 1999-06-15
AU2777092A (en) 1993-05-03

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